DESCRIPTION: Coronary artery disease (CAD) is a major cause of morbidity and mortality in the US. Since half of those who suffer myocardial infarctions (MIs) and sudden death are previously asymptomatic, studies of individuals with atherosclerosis but without symptoms will contribute to understanding sub clinical disease. Coronary artery calcification (CAC), part of the atherosclerosis process, can be accurately and non-invasively quantified by electron beam computed tomography (EBCT). CAC quantity correlates with plaque area and predicts coronary artery stenosis better than established CAD risk factors. In the first nine years of our study, we determined the distribution of CAC quantity in 1,647 asymptomatic adults (including 956 sib pairs) from Rochester, MN who were not physician-referred, self-referred, or high risk and had no history of MI, stroke, or revascularization (i.e., asymptomatic). Specific genes contributed to inter-individual variation in presence and quantity of CAC after accounting for traditional CAD risk factors. In pilot studies, CAC quantity significantly predicted MI, CAD death, and revascularization and CAC quantity increased 24 percent per year with considerable inter-individual variation in extent of change in quantity of CAC. New CAD risk factors (i.e., fibrinogen, C-reactive protein ad antibodies to infective agents) predicted CAC quantity after accounting for traditional CAD risk factors. These findings motivate the aims of this continuation application to determine whether CAC quantity and/or change in CAC quantity predicts clinical events as well as to locate genes that influence progression of CAC quantity. Our proposed study takes advantage of already available EBCT measures of CAC quantity, traditional CAD risk factors, more than 60 candidate genes and 375 highly polymorphic anonymous markers and stored samples to be used for new CAD risk factors. New data will be collected on clinical endpoints on all 1,647 asymptomatic adults as well as progression of CAC quantity in a subsample of 1,000 asymptomatic adults (550 sib pairs). We will determine whether CAC quantity predicts clinical events after 7.5 years of active follow-up (Aim 1), determine whether change in CAC quantity over 7.5 years predicts future events after an additional 2.5 years of follow-up (Aim 2), identify genetic determinants of change in CAC quantity, and assess whether these genes act through measurable CAD risk factors (Aims 3 and 4). Understanding relationships between sub clinical atherosclerosis and future events, progression in sub clinical atherosclerosis and future events, as well as factors predicting progression of sub clinical atherosclerosis will improve early identification of individuals who will benefit most from existing or new interventions.